Abstract

The integration of somatosensory information is generally assumed to be a function of the central nervous system (CNS). Here we describe fully functional GABAergic communication within rodent peripheral sensory ganglia and show that it can modulate transmission of pain-related signals from the peripheral sensory nerves to the CNS. We found that sensory neurons express major proteins necessary for GABA synthesis and release and that sensory neurons released GABA in response to depolarization. In vivo focal infusion of GABA or GABA reuptake inhibitor to sensory ganglia dramatically reduced acute peripherally induced nociception and alleviated neuropathic and inflammatory pain. In addition, focal application of GABA receptor antagonists to sensory ganglia triggered or exacerbated peripherally induced nociception. We also demonstrated that chemogenetic or optogenetic depolarization of GABAergic dorsal root ganglion neurons in vivo reduced acute and chronic peripherally induced nociception. Mechanistically, GABA depolarized the majority of sensory neuron somata, yet produced a net inhibitory effect on the nociceptive transmission due to the filtering effect at nociceptive fiber T-junctions. Our findings indicate that peripheral somatosensory ganglia represent a hitherto underappreciated site of somatosensory signal integration and offer a potential target for therapeutic intervention.

Figure 5

(A and B) Focal DRG application of GABA (200 μM, ~0.5 μl/h) via osmotic minipump significantly alleviated mechanical (A) and thermal (B) hyperalgesia produced by the plantar injection of CFA. (C and D) Similar to A and B but a chronic constriction injury (CCI) was applied to a sciatic nerve instead of CFA injection. (E–H) Similar to A and B but GAT1 inhibitor NO711 (200 μM, ~0.5 μl/h) was applied via the minipump implant instead of GABA. In A–H, the CFA/CCI procedure and the minipump implantation were performed at the same time. Number symbols indicate significant difference between saline and drug data sets: #P < 0.05, ##P < 0.01, ###P < 0.001; asterisks indicate the difference between groups within the corresponding time point: *P < 0.05, **P < 0.01, ***P < 0.001 (2-way ANOVA with Bonferroni correction for saline vs. drug comparison or 1-way ANOVA with Fisher LSD post hoc test for comparison between the groups). Number of experiments is indicated as n in each panel.